HU194825B - Process for producing 2-oxindol-1-carboxamide derivatives - Google Patents

Abstract

Covers oxindole intermediates, and their preparation, of the formula: wherein X and Y are certain stated substituents or may when taken together form certain ring structures, and R is H or -COR¹ where R¹ is alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, (thiophenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -(CH₂)_n-Q-R' where n is 0, 1 or 2, Q is a divalent radical which is a specified heterocycle, and R° is H or alkyl; and also covers the hydrolysis of the compounds (II) to end products of the formula:

Description

The present invention relates to a process for the preparation of 2-oxindole 1 carboxamides by reacting 2-oxindole with chlorosulfonyl isocyanate to form a new N-chlorosulfonyl 2-oxindole 1 carboxamide which is subsequently hydrolyzed to 2-oxindole-1-carboxamide. The above 2-oxindel-1-carboxamides are useful intermediates for the production of analgesic and anti-inflammatory agents.

Reactions of chlorosulfonyl isocyanate with various nucleophilic compounds, including amines, to prepare the corresponding N-chlorosulfonyl amido / CISO2NHCO / derivatives and hydrolysis of the derivatives concerned to amides are described in the following publications. Count, Angew. At Chem Inter. Edit., 7,175 (1968); Rasmussen et al., Chem Rev. 389-390 (1976) and Szabó, Aldrichimica Acta, 10, 23 (1977).

The preparation of 2-oxindole-1-carboxamides by ring closure with the corresponding 2-ureidophenyl / acetic acid, such as trifluoroacetic anhydride / trifluoroacetic acid, was simultaneously reported by Baul B Kadin and published after the date of priority. -Substituted 2oxindole 1-carboxamides as analgesic and anti-inflammatory agents', DPC / Ph / 6795A. U.S. Pat.

The improved process of the present invention provides 2-oxindole-1-carboxamides of formula (III) from readily available starting materials in good yield and high purity.

The process of the present invention allows the preparation of 2-oxindole-1-carboxamides by reacting 2-oxindole with chlorosulfonyl isocyanate to yield a new intermediate of structure N-chlorosulfonyl-2-oxindole 1-carboxamide which is hydrolyzed to 2-oxindole-1-carboxamide. The process, intermediate, and final product are illustrated in Formula 1, wherein

X is hydrogen, fluoro, chloro, bromo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, nitro, phenyl, C 2-4 alkanoyl, benzoyl or tenoyl,

Y is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 alkoxy, or

X and Y are taken together to form methylene dioxide attached to adjacent carbon atoms,

R is hydrogen or -CO-R ¹ in which

R ^{1 is} furyl, thienyl or thienyl (C 1 -C 3) alkyl.

Compounds of formula III wherein R is hydrogen are valuable intermediates represented by formula IV for the production of analgesic anti-inflammatory compounds wherein Y, Y and R are as defined above

Preferred compounds of formula (IV) are those wherein 2 is X or Y is hydrogen and the other is 5 or 6-chloro, fluoro or trifluoromethyl;

or b / X 5-chloro or 5-fluoro and Y 6-chloro or 6-fluoro. The compounds exhibit a higher level of analgesic anti-inflammatory activity than the other compounds of formula IV.

Thus, the process of the present invention is useful for the preparation of compounds of formula IV having analgesic and anti-inflammatory activity, wherein Y, Y and R are as defined above. These compounds are derivatives of the 2-oxindole of formula (V), a two-ring amide. In particular, the analgesic and anti-inflammatory compounds have a carboxamide - (- (C 0-O) -NH ₂ ) substituent at the 1-position and a -C (O) -F in the 3-position with 2-oxindole; and the benzene ring may be substituted with additional X and Y groups. X and Y may be the monovalent substituents as defined above, or X and Y - when located on an adjacent carbon - may be a benzene ring, -OCH ₂ O - methylenedioxy.

Compounds of formula (III) may be prepared from the corresponding 2-oxindole (1) ^. in the two steps shown in formula 1. The desired oxindoles (R »H) can be prepared by methods known to those skilled in the art. The preparation of various 2-oxindoles is described in the following literature:

"The Chemistry of Heterocyclic Compounds", Indoles, Part 2, edited by Houlihan, Wiley-lntersci cnce, N.Y., p. 142-143 (1973); Rodd's Chemistry of Carbon Compounds, 2nd edition, edited by S. Coffey, IVB-A. Vol. 448-460 (1973), by Walker, J. Am. Chem. Soc., 77, 3844-3850 (1955), by Wright, et al., J. Am. Chem. 224, 1956; McEvoy et al., J Org Chem 38, 3350 (1973); Gassman et al., JOrg Chem. 42, 1340 (1977); Beckett et al., Tetrahedron 24, 6093 (1968), Profiva et al., Coll. Czech. Chem Comm 44,2108 (1979); and U.S. Patent Nos. 3,882,236, 4,006,161, and 4,160,032. In addition, the preparation of some substituted 2-oxindoles is described below.

The starting materials of formula (I) wherein R-CO-R, wherein R ¹ is as defined above, are prepared by acylating a suitable compound of formula (I) wherein R is hydrogen. Acylation procedures are well known to those of ordinary skill in the art. For example, the acyl moiety -CO-R ¹ is introduced by reacting a compound of formula (I) with an active derivative of a suitable acid of formula RC / sO / -OH

-2194825 in lower alkanol / e.g. ethanol / an alkali metal salt of a solvent with a few unsaturated alkanols, e.g. sodium ethoxide, in the presence of conventional methods. The acid RC (-O / -OH) is a legal derivative of a signal which is useful for the anhydrides of formula R ¹ C / O / OC / -O / R, R-Cl

Cl-O / R ³ and R ^{1 are} C / O / OC / -O / OR ⁴ and further are simple alkyl esters of the formula R ¹ -C / O / -OR ⁴ , wherein R ^{3 is a} bulky lower alkyl group. like it's cool! and R ^{4 is a} lower molecular weight alkyl group. Usually a small excess of the acid of formula R ¹ -C / = O / -OH is used and there is 1 2 molar equivalents of the alkoxy salt relative to the anhydrous derivative of the word RC / O / OH. Reaction of an acid derivative of the formula R CMO / -OH with a compound of the formula (I) wherein R is hydrogen is usually initiated at 0 to 25 ° C, but is usually carried out at about 50 to 130 ° C, preferably about 80 ° C. the temperature to complete the reaction Under these conditions, the reaction time is usually from a few hours, e.g. It can range from 2 hours, some na pig, eg 2 days. Subsequently, the reaction mixture is cooled, diluted with excess water and acidified with the product of formula (I) wherein R is hydrogen, either by filtration or by conventional liquid dextraction.

The first step of the process, i.e. the reaction of the corresponding 2-oxindole with chlorosulfonyl isocyanate, is carried out in an inert solvent medium, for example, which is neither with the chlorosulfonyl isocyanate nor with the 2-oxindole-1 chlorosulfonamide of formula (11). responds. The solvent does not necessarily have to completely dissolve the reaction components. Representative solvents include diaikitic alcohols such as diethyl ether, diisopropyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, chlorinated hydrocarbons such as methylene chloride or chloroform and acetonitrile.

The reaction is conducted at a general temperature of between 20 ° C and the boiling point of the solvent used. Temperatures between 25 ° C and 110 ° C are generally advantageous Low temperatures can be up to 70 ° C if desired, although the use of temperatures below 0 ° C is generally avoided for practical reasons

The 2-oxindole and the chlorosulfonyl isocyanate are usually reacted in a ratio of equimolecular to 30% excess of chlorosulfonyl isocyanate, i.e., 1: 1 to 11.3. The use of a large excess of chlorosulfonyl isocyanate does not appear to be advantageous and is not used economically.

The chlorosulfonamide derivatives of formula (II) thus prepared can be isolated, if desired, or can be converted to compounds of formula (III) in the same reaction without isolation, by isolation of intermediate chlorosulfonamide compounds of formula (II) by methods known to those skilled in the art. for example, filtration, evaporation of the solvent or extraction.

The hydrolysis of the chloro sulfone amido derivatives of the formula (II) is carried out by treating the compound alone or without isolation with water, aqueous acid or aqueous alkaline solution. In general, water is the preferred hydrolyzing agent, even if the hydrolysis takes place in a two-phase system. The rate of hydrolysis is fast enough to rule out any solubility problems with the reactant components. In addition, for large volume reactions, the use of water alone is much more economical. like any other hydrolysis method.

The use of an aqueous solution of an inorganic or organic acid as a hydrolyzing agent sometimes eliminates the biphasic reaction system. This is often the case with aqueous acetic acid. The amount of acid is not a critical parameter in the hydrolysis step. This equimole may range from less than or equal to the amount consumed. The concentration of the acid used is also not critical. Generally, when an aqueous acid solution is used in the hydrolysis step, 0.1 mol of acid / mol relative to the compound of formula II is used. 3 mol of acid / mol may be used. A molar concentration of 1 to 6 molar acids is used in its bowl to facilitate treatment. The use of aqueous acid is often then resorting if ve Gyula of the / 11 / general formula ¹ is isolated and a single phase hydrolysis mixture we desire. Typical acids are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, citric acid and benzoic acid.

Compounds of formula IV may be prepared from the corresponding 2-oxindole carboxamide compound of formula III wherein R is hydrogen, X and Y are as defined above. This is accomplished by introducing the -C (-O) -R ¹ substituent into the 3-position of the 2-oxindole core. The substituent C / O / R is introduced by reacting the compound of formula (III) with an active derivative of the carboxylic acid R ¹ C / = O / ΌΗ. The reaction is carried out by reacting a compound of formula (III) in an inert solvent with a molar equivalent or slightly higher amount of the active derivative of a carbonic acid RC / 0 / OH in the presence of 1 to 4 equivalents by weight of a basic agent called an inert solvent. In practice, polar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide are generally used. For example, both halogenides, such as acid chlorides, can be successfully used in the preparation of RC / 0/0 C7-0 / -R '.

Symmetric acid anhydrides of the formula -3194825 nos are mixed mixed acid anhydrides of the formula R 1 -C / O / OC / O / R ³ with a low molecular weight carboxylic acid, wherein R ^{3 is a} bulky lower alkyl group such as t-butyl and mixed R'-C / O. Carboxylic acid anhydrides of the formula (OC / -O / -OR), wherein R is a low molecular weight alkyl sport. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiol phenyl esters) and 2,4,5-trichlorophenyl esters and like. Besides this, in cases where R ¹ h ^ of heteroaryl / for example, furyl / sometimes ^R1 CMO / ^OR4 formula simple alkyl esters, wherein R ⁴ low molecular weight alkyl powder / example ethyl / may be used né if as R - C / -0 / ^-0-R4 of formula assets acid derivatives, in order that the C / -0 / ^R1 delivered in a substituent on the carbon atom at the 2-oxindole 3 as a compound / 111 /, wherein R is hydrogen; .

A wide variety of basic agents can be used to react a compound of formula (III) wherein R is hydrogen and the active derivative of an acid of formula R ¹ C / -O / OH. In any case, the preferred basic agents are tertiary amines such as triethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4 / NN-dimethylamino / piperidine.

The reaction of the compound (III) in which R is hydrogen and the active derivatives of the acid of the formula R-C (-O) -OH is generally carried out at a temperature in the range of from 10 to 25 ° C. The reaction time in a pellet is between 30 minutes and several hours. At the end of the reaction, the reaction medium is usually diluted with water and acidified, and then the product is recovered by two filtrations. The product may be purified by conventional techniques such as recrystallization

The demonstration of the analgesic effect of the compounds of formula (IV) was investigated in mice by relieving abdominal tension that can be achieved with 2 phenyl 1,4-benzoquinone / PBQ / batch. The method used is based on Siegmund et al., Proc. Soc. Exp. Bioi Med, 95,729-731,1957, but adapted for greater efficiency (see also Milne and Twomey, Agents and Actions, 10, 31 37, 1980). In these experiments, male Carworth mice of albino strain CF-1 were weighed between 18 and 20 g. All mice were fasted overnight prior to drug administration and examined.

Compounds of formula (IV) are dissolved or suspended in a mixture of 5% ethanol, 5% emulphor 620 (a mixture of polyoxyethylene fatty acid esters) and 90% saline. The vehicle also served as a control. Doses varied on a logarithmic scale / pl. . .. 0.32, 1.0, 3.2, 10, 32 ... mg / kg /. The route of administration was oral, at concentrations sufficient to inject a constant volume of 10 ml / kg per mouse. The method described by Miine and Twomey was used to determine efficacy and potency. The mice were given the compounds orally, and one hour later, 2 mg / kg PBQ was administered intraperitoneally. Individual mice were then immediately placed in heated lucite chambers and abdominal contractions were measured five minutes after the PBQ injection and for the next five minutes. The analgesic effect (% MPE) was calculated based on abdominal contractions compared to control animals tested on the same day. At least four of these determinations (N > 5) provide data for dose response MPE50 calculation, which is the best estimate of the dose that reduces abdominal contractions by 50% compared to controls.

The anti-inflammatory activity of the compounds of formula (IV) was investigated in rats by a test method based on a standard carragenin-induced edema test in rats / Winter et al., Proc. Soc Exp Bioi. Med., 111, 544 (1963).

Non-anesthetized adult albino rats weighing 150 to 190 g were counted, weighed, and horizontally marked with ink on their right ankle. Each man tube was dipped in mercury to the exact level indicated by the ink. The mercury was in a glass cylinder connected to a Statham pressure transducer. From the converter through the output control unit to a micro voltmeter. The volume of the shear displaced by the immersed paw was read. The drugs were administered by gavage. One hour after drug administration, 0.05 ml of a 1% carrageenin solution was injected into the foot of the marked paw to induce edema. Immediately afterwards, the volume of the injected foot was measured. An increase in foot volume three hours after injection was an individual response.

The compounds of formula IV, by virtue of their analgesic activity, are useful in the treatment of acute pain, postoperative pain and traumatic pain in mammals, including humans. Due to their anti-inflammatory activity, the compounds of the present invention can be used chronically in mammals, including man, for the treatment of inflammatory diseases such as arthritis, in particular rheumatoid arthritis.

When a compound of formula (IV) is used for any of the above purposes, it can be administered to a mammal alone, or preferably in combination with pharmaceutically acceptable carriers and diluents, in the form of a pharmaceutical composition which includes oral or peroral administration according to standard pharmaceutical practice.

-4194825 can be administered by intramuscular, intraperitoneal, subcutaneous and topical application.

In a pharmaceutical composition comprising a compound of formula IV, the ratio of the weight of the excipients to the active ingredient is generally from 1: 4 to 4, preferably from 1: 2 to 2: 1. In each case, the ratio chosen will depend on factors such as the solubility of the active ingredient, the intended dose and the route of administration.

The compound of formula (IV) may be administered orally, in the form of tablets or capsules, or as an aqueous solution or suspension. The carriers commonly used in the tablets include lactose and corn starch. Sliding agents such as magnesium stearate are also generally added. Diluents useful in the form of encapsulation include the dairy age and dried corn starch. Where aqueous suspensions are required for oral use, the active ingredient may be combined with emulsifying and suspending agents and certain sweetening and / or flavoring agents may be added if desired. For intramuscular, int raperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, the pH of the solution is adjusted, and the solution is buffered for intravenous use, the total concentration of the solutes being checked to make the preparation isotonic.

The daily dose to be determined by the prescribing physician when using any of the compounds of Formula IV will naturally vary with the age, weight and response of the patient and the severity of the patient's symptoms. In any case, when used for acute analgesia if the effective dose is in most cases between 0.1 and 1.0 g, as needed / for example every four or six hours / In chronic use as an anti-inflammatory drug, the effective dose will usually be between 0.5 and 3.0 g daily On the other hand, in some cases it may be necessary to use this data outside the boundaries.

The following examples serve to illustrate the process of the invention. No attempt was made to increase the yield to the optimal level for the examples and formulations

/. example

Oxindol V carboxamide

To a solution of oxindole (0.94 g, 7.1 mmol / ether / 30 mL), chlorosulfonyl isocyanate / 1.20 g,

8.4 mmol (a) was added and the reaction mixture was stirred at room temperature for 20 hours. The ether was evaporated in vacuo, water (10 ml) and 1 N hydrochloric acid (10 ml) were added and ethyl acetate (125 ml) was added and the mixture was stirred for 1 hour. stirring. The ethyl acetate layer was separated, washed with n hydrochloric acid (1 x 50 mL) and brine (2 x 100 mL) and dried over magnesium sulfate. Evaporation of 0.97 g (77%) of crude product gives two crude products which are recrystallized from ethanol to give 0.18 g of m.p. 178-130 ° C.

Example 2

2Oxindole 1 carboxamide

Oxindole (5.86 g, 44 mmol / toluene / 160 mL) was subjected to azeotropic distillation for one hour to dry the toluene. Chlorosulfonyl isocyanate / 7.47 g,

52.8 mmol /. Immediately, hydrochloric acid is formed. The mixture was refluxed for 15 minutes and then cooled to room temperature. To the cooled solution (initially va (as hydrochloric acid was formed / water / 50 mL) was added and the mixture was stirred for 1.5 h. The resulting solid was collected by filtration and dried (4.1 g). The filtrate was extracted with ethyl acetate / 100 ml /, the resulting extract was washed with brine (2 x 100 ml) and dried over magnesium sulfate.

4.16 g of a solid are obtained. The combined solids were recrystallized from acetonitrile (200 mL) and concentrated under reduced pressure to 75 mL. The resulting small amount of amorphous material was filtered off, the filtrate was clarified and inoculated under reduced pressure to 50 ml. The precipitated dark red crystals were filtered off and dried (3.0 g, 38%). The crystalline product is identical to the product obtained in Example 1.

Example 3

2- Oxindo! / carboxamide

To a slurry of 2-oxindole (13.3 g, 0.10 mol) in toluene (150 ml) was added chlorosulfonyl isocyanate (15.6 g, 0.11 mol) and the reaction mixture was heated on a water bath for ten minutes. Within three minutes, a clear solution formed, followed almost immediately by precipitation. After cooling on ice for 30 minutes, the solid precipitate was filtered off and air-dried.

The chloro sulfone amido intermediate thus obtained was added to a 2: 1 mixture of acetic acid / water (240 mL) and the resulting slurry was heated on a water bath for 10 minutes. Cool on ice and filter the east treated solid and air dry. The mother liquor was evaporated to a paste and filtered to give 1.2 g of product. The combined solids were recrystallized from 250 mL of ethanol. 11.48 g (65%) of product are obtained. The product is the same as the product of Example 1

Fluorine 5 methyl 2-oxindole-1 carboxamide

Following the procedure of Example 2, the title compound was prepared from 6-fluoro-5-methyl 2-oxindole / 10 g, 6.0 mmol / chlorosulfonyl isocyanate / 10 03 g, 7.3 mmol / toluene / 30 ml / Water (5 ml) was used for the hydrolysis step. Yield: 0.58 g, 46%. Mp: 200 - 203 ° C.

Analysis calculated for C10 H9 N2 O2 F: C, 57.69; H, 4.36; N, 13.46. C, 57.02; H, 4.41; N, 12.85%.

-5194825

A sample of the chlorosulfonamide intermediate was hydrolyzed prior to hydrolysis and subjected to mass spectrometric analysis to determine mass accurately.

C 10 H 8 N 2 O 4 SCI: 307 9848

Spreadsheet

ΙΟ

5-13. example

Your deputy made 2-oxindole 1 carboxamides

The compounds in the table on the next page were prepared from the appropriately substituted oxindoles 2 according to the procedure of Example 3.

Example 2-oxindole CSI g Solvent we Intermediate Hydrolysis in ml of acetic acid X Y g g op 5 5-CH3 H 11 51 122 150 16 120/160 6 5-OCH; H 8 15 7.78 100 84 80/40 7 4-Cl H 5 03 4 67 85 149-50 45/25 8 5-Cl H 100 93 200 158 163 50/5 Q 6-Cl H 4 18 389 85 165-6 / decomposes / 41/21 w 5-F H 100 103 100 16 50/100 11 5-CF ;, H 4 4 3.4 45 6 5 20/40 12 4-CH3 5-CH3 4.8 4 7 45 88 25/50 13 5-CH 6, -CHj 1 e 1 6 15 28 8Ί7

Continue Table

Example 2 Oxindole 1 Carboxamide Product g Yield Op c Sami loti H Analysis N C tatait H N 5 7.3 49 215 6 / decays / 6 73 70 191 2 7 3 64 53 201 2 ° 51 32 3:35 13 30 51.04 3 26 13 24 8 98 -168 211 / decomposes / 51 32 3:35 1330 51.14 3 48 13 21 9 4 09 78 221 2 / decomposes / 51 32 3 35 13:30 51 97 3:30 13:31 10 6.7 52 3 198 55.67 364 1443 56.25 3.79 14:53 n 3.4 63 3 214 5 49 19 2 89 11:48 48.90 305 11:50 12 08 08 66 6 222 / decomposes / 6469 5 92 13.72 64 57 5 94 13 64 13 1 3 637 214 5 64 69 5 92 13.72 64 52 6 67 13 68

English a2a?

CSI chlorosulfonyl isocyanate recrystallized from eyanol recrystallized from acetonitrile recrystallized from acetic acid

Example 14

5,6-Methylene thioxt-2-oxindole 1 carboxamide

5,6-Methylenedioxy-2-oxindole 1 Carboxamide was prepared by reaction of 5.6 methylenedioxy-2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis using the procedure described in Example 3 after recrystallization from acetic acid during product / decomposition. / 237238 C is a molten example

Methylthio 2 oxmdol-1-carboxamide

A slurry of methylthio 2 oxindole (6.0 g, 0.033 mol) in acetonitrile (60 ml) was added to chlorosulfonyl isocyanate (5.66 g, 0.04 mol) at 5-10 ° C. The reaction mixture is stirred for one hour. Water (100 ml) is then added and the mixture is stirred vigorously for ten minutes. The aqueous solution was extracted with ethyl acetate (600 mL), washed successively with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a gray solid which was recrystallized from acetonitrile. Yield: 3 g. Total yield: 3.71 g (50.6%), m.p. 176,179 ° C

Example 16

5.6 Dimethoxy 2 oxindole-1-carboxamide

The title compound was prepared according to the procedure described in Example 16 from 5.6 dimethoxy 2-oxindole (8.0 g, 0.042 mol), chlorosulfonyl isocyanate (7.08 g, 0.05 mol) and acetonitrile (75 ml). The crude product obtained by evaporation of the ethyl acetate extract was crystallized from 1 liter of acetonitrile / acetic acid (602 g / 60%); mp: 206.5-209 ° C.

Similarly, 5,6-methylone-dioxy-2-oxindole 1 carboxamide is prepared from 5,6-methylenedioxy-2-oxindole.

example

6-Trifluoromethyl 2-oxindole I carboxamide

6-trifluoromethyl from 2-oxindole / 8.0 g,

Chlorosulfonyl isocyanate (6.65 g, 0.047 mol) was added to the slurry from 04 M (80 ml) of acetonitrile (80 ml) and the mixture was stirred for 45 minutes. Water (100 ml) was added and the aqueous solution was stirred for 1 hour. The resulting precipitate was filtered and recrystallized from acetonitrile to give 0.92 g of the title compound. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 mL), drying of the extract over magnesium sulfate and reduced pressure gave a further product, which was recrystallized from Acetonitrile to give 2.2 g more product.

Combining the mother liquors of the acetonitrile recrystallizations and evaporating it under reduced pressure yielded additional product. Overall yield 4.97 g (51%), mp 207.5-210 ° C.

18 23 Example

By repeating the procedure described in Example 17 with the appropriate substituted 2-oxindoles, the compounds of formula (III) listed below are obtained, where R is a hydrogen atom:

-6194825

Ι2

Tatiiaza!

rQida 2 OfinÖQ! > Y 9 CSI c Solvent ml Intermediate Rooms op C Hydrolysis Hydrolysis agent, 'water purifier 2-oxindole-1-carboxamidl coins g mining 5r * 3 OP C B.C 4 5 H 225 2 26 25 20 1.62 56 181-4 19 6-F H 1:06 099 15 141 5-145 15 1 21 94 5 191.5-194 2C 6-Er K 375 2 97 40 168-161 40 2 50 58 205-8 21 5-NO? H 1 1 1:13 30 232-235 5 052 38.5 201-5 Z.C. 5-F 6 <i 1 59 1 4? 55 ^J 20 10.02 52 ' 22Θ-31 23 5-F P-6 5 0 £ 98 13 15 2 60 72 198-201

Waijia'sza · CS! chlorosulfonyl isociar.a!

a Toluene was used as solvent b NMR spectrum showed that the isomer 4-chloro-5-fluoro-2-oxindole-1-carboxamide was also formed, the starting material was a mixture of isomers c the toluene solvent oeparic acid yielded 0 59 g.

Example 24 (2 Furoyl) -6-fluoro-2-oxindole-1-carboxamide

By essentially following the procedure of Example 17, the title compound was prepared in a 17% yield from 3- (2-furoyl) -6-fluoro-2-oxindole (0.30 g, 1.2 mmol) and chlorine. sulfonyl isocyanate (0.20 g, 1.4 mmol, acetonitrile (15 mL) and water (10 mL)). Yield: 0.060 g, mp 231-235 ° C.

example

Substituted 2-oxindole-1-chlorosulfone amides

The corresponding substituted 2-oxindole is reacted according to the procedure described in Example 15. Prior to the hydrolysis step, the intermediate chloro sulfonyl derivative is isolated from the reaction mixture by evaporation in a small volume, if no solid precipitate is formed. The thus prepared intermediate sample was used for the exact determination of the number of the following two compounds of formula A / Ha /:

2 X oxiridol Y CS Solvent we Intermediate g g Formula Exact weight 6 F H 1 5 1.70 15 Cr., H ₆ N ^ O 4 FSCI 291 9721 6 cf ₃ H 0.5 0.35 10 ^a C 0H6N2O4F3SCI 341.3693 5 F 6 Cl 1.59 1.42 55 ^a CyH ₆ N ₂ O4FSCl2 326.9340 5 noo H 1.75 0.35 55 ^a CuH ₆ H ₃ O ₆ SCI 3189675 6 Br H 0.40 0.31 5 ^a C ₃ H ₆ N ₂ O ₄ SBrCl 351.8863 5 and ₃ 6 OCH ₃ 1.0 0.85 12 C _i H, _i N ₂ OeSCI 344.0034 6 SCH ₃ H 0.20 0:18 3 ^a C ioH9N ₂ 04S ₂ CI 319 9636 4 SCH ₃ H 0.20 0.18 3 ' C ioHgN ₂ 04S ₂ Cl 319 9696 6 F 5 CH ₃ 0.16 0.14 10 ^a Ci ₀ H ₈ N ₂ O4FCIS 307 9848

Explanation:

CSI chlorosulfonyl isocyanate;

the solvent used is toluene.

example

6 ~ Fem! -2-oxindole-carboxamide to a mixture of 100 ml of toluene, 25 ml of tetrahydrofuran and 4.5 g / 21.5 mmol of 6-phenyl-2-oxindole at 5 ° C with stirring 2.2 ml / 25.8 Chlorosulfonyl isocyanate (0 mmol) was added and the mixture was stirred at 0-5 ° C for an additional hour and water (100 mL) was added. The solid was filtered off and added to a mixture of glacial acetic acid (40 mL) and water (80 mL). The resulting solution was heated at 100 ° C for one hour, cooled and filtered. After drying the residue, 3.1 g of the title compound, m.p. 188-189 ° C

Example 27

5-Benzoyl-2-oxo-indole-1-carboxamide

10.1 g (42 mmol) of 5-benzoyl-2-oxindole,

A mixture of chlorosulfonyl isocyanate (4.4 mL, 51 mmol) and tetrahydrofuran (300 mL) was stirred at room temperature for 6 hours and the solvent was distilled off in vacuo. Glacial acetic acid (150 mL) and water (300 mL) were added and the resulting solution was refluxed the acrylic mixture was cooled and the supernatant was removed by dexanting. The gummy residue was triturated with acetonitrile. The resulting solid was filtered off and recrystallized from a 1: 1 mixture of n-propanol and acetonitrile to give 4.1 g of the compound of dm as a solid, m.p. 210-211 ° C.

Example 28

Reaction of 5-acetyl-2-oxindole and 5- / 2-tenoyl / 2-oxine dcl with chlorosulfonyl isocyanate followed by hydrolysis with aqueous acetic acid essentially as described in Example 28 gave the following compounds.

5-acetyl-2-oxindole-1-carboxamide, 34% ki60 (m.p. 225 DEG C. (dec. Dec.) / Acetonitrile and

5- / 2 tenoyl / 2 oxindole 1 carboxamide, 5 '% yield, op 200 C / decomposition / // methanol from acetonitrile /

-713 polta

3-i'-2-Tennoylb chloro 2 oxmdel 1-carboxamide

To a slurry of 1.5 g / 5.4 mmol / 3/2 tenoyl / 5 chlorooxindole and 15 mL dry acetonitrile was added 0.52 mL (5.9 mmol) of chlorosulfonyl isocyanate and the reaction mixture was stirred at room temperature for two hours. Take a small sample, filter, and evaporate in vacuo to give a small amount of N-chlorosulfonyl 3/2-tenoyl / -5-chloro-2-oxindole 1-carboxamide (m.p. 166,169 C). After stirring for 1 hour, the reaction mixture is poured into 50 ml of ice-cold 1 N hydrochloric acid and the resulting solution is stirred for 20 minutes. The precipitated yellow solid is filtered off, first with water and then with isopropyl ether, and recrystallized from glacial

200 mg, first generation, m.p. 213 215 C. Second generation solid precipitates from mother liquors of first generation. After filtration, 470 mg of product is obtained as a second generation of the title compound. It is recrystallized from glacial acetic acid and recrystallized from glacial acetic acid. 280 mg, m.p. 232-234 Example C

Chlor-2 oxindole

Add 100 ml / 0.55 / 5-chlorine isatin to 930 ml of slurry in 40 ml / 0.826 mol / hydrazine hydrate to give a red solution. The solution was heated under reflux for 3.5 hours while a precipitate formed. The reaction mixture was stirred overnight, then the precipitate was filtered off and dried in vacuo to give 105.4 g of the 5-chloro-3-hydrazone 2 oxindole as a yellow solid.

The dried solid was added in portions to a solution of 125.1 g of sodium ethoxide in 900 ml of absolute ethanol for 10 minutes. The crude solution was refluxed for 10 minutes and evaporated in vacuo to give a gummy solid. The gum was dissolved in 400 mL of water and the resulting aqueous solution was clarified with activated carbon and poured into a mixture of 1 L of water and 180 mL of concentrated hydrochloric acid in ice granules to precipitate a brown solid which was washed with diethyl ether. 9 g were obtained, m.p. 193-195 ° C (with decomposition).

In an analogous manner, 5-methylisaline was converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate followed by reaction with ethanolic sodium ethoxide solution. The product melted at 173-17 ° C.

Oelde

-l.b-Dimethyl 2-oxindo! and 5.6 dimethyl 2-oxindole

3,4-dimethylaniline with chloral hydrate and hydroxylamine! on page 327 of the Organic Synlheses' Collective Volume, page 8! 4 lei t! Converted to 3,4-dimethyl-isonitrosoacetanilide. 3-I-dimethyl-isonitrosoacetanilide was prepared by Baker el al in J of Org Chem. cyclization with benzoic acid to give 4.5-dimethyl-isatin / op.:255-226 ° C and 5-dimethyl-isatin / op. 217-218 ° C /

4,5-Dimethylisatin is essentially hydrolysed as described in Example 30 to sodium 4,5-dimethyl-2-oxindole (m.p. 245.5-247.5 ° C) followed by sodium ethoxide in ethanol.

Similarly, essentially as described in Example 30, 5,6-dimethyl-isatin was reacted with hydrazine hydrate followed by ethanol with sodium ethoxide to give 5,6-dimethyl-2-oxindole / op.

196.5-198 ° C

Example 32

4-clot -2-oxindole and 6-chlorooxindole

A.Zonitroso-3-chloroacetanifide

To a solution of 113.23 g / 0.686 mol / chloral hydrate in 2 liters of water, 419 g / 2.95 mol / l sodium sulfate followed by 89.25 g / 0.70 mol / 3-chloroaniline, 62 ml concentrated hydrochloric acid and 500 ml of stock solution were added. A thick precipitate formed. The reaction mixture was then added with stirring to a side of 155 g (2.23 mol) of hydroxyamine in 500 ml of water. While stirring, the mixture was warmed slightly to 60-75 ° C and the mixture was stirred for 6 hours while adding an additional 1 liter of water to facilitate stirring. The reaction mixture was cooled and the precipitate was collected by filtration. -3-Cyanoacetanilide is obtained.

B. 4-Chloro-isatin and 6-chloro-isatin

To 775 ml of concentrated sulfuric acid, preheated to C, is added 136 g of isonitrosoacetanilide with stirring so that the temperature of the reaction mixture is maintained at 75-85 ° C. When the total amount of solid was added, the reaction mixture was heated to 90 ° C. Maintain this temperature for 30 minutes. Then cool the mixture and pour slowly over about 2 liters of ice on stirring. Add additional ice if necessary to maintain the temperature below room temperature. A reddish-orange precipitate was formed, which was filtered, washed with water and dried. The resulting solid was slurried in 2 L of water and diluted with ca. 700 mL of 3N sodium hydroxide. 120 mL of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added. The precipitated solid is filtered off, washed with water and dried to give 50 g of crude 4-chloro-isatin. The filtrate after filtration of 4-chloro-itazine is adjusted to pH 0 with concentrated hydrochloric acid to give additional precipitate. dried to give 43 g of crude 6-chlorodatin

The crude chlorisatin 4 was recrystallized from acetic acid to give 43.3 g of 258-259 'C melt.

-8194825

Recrystallization of crude chloroisatin 6 from acetic acid gave 36.2 g of melting point 261-262 ° C.

C. 4-Chloro-2-oxindole

To a slurry of 43.3 g of 4-chloro-isatin in 350 ml of ethnol was added 17.3 ml of hydrazine hydrate, and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled and the precipitate was filtered off with 43.5 g of melting point 235236C. -chloro-3-hydrazono-2-oxindole was added to a solution of sodium g in 450 ml of anhydrous ethanol with stirring, and 43.5 g of 4-chloro-3-hydrazono-2-oxindole was added and the resulting solution was refluxed for 30 minutes. concentrated to a gum which is dissolved in 400 ml of water and clarified with activated carbon. The resulting solution was poured into a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, dried and recrystallized from ethanol to give 22 chloro-2-oxindole (22.4 g), m.p. 216-218 ° C.

D. 6-Chloro-2-oxindole

Reaction of 6-chloro isatin (36.2 g) with hydrazine hydrate essentially as described in (C) above followed by sodium ethoxide in ethanol gave 14.2 g of 6-chloro-2-oxindole melting at 196-198 ° C.

5,6-Dilluor-2-oxindole

In a manner analogous to Example 32 A and B, 3,4-difluoroaniline is reacted with chloral hydrate and hydroxylamine to give 5,6-difluoro isatin by ring closure. This, analogous to that described in Example 30, is reacted with hydrazine hydrate followed by sodium methoxide in ethanol to give the title compound, m.p. 187-190 ° C.

- Fluorine -2-oxindo!

To a solution of 11.1 g / 0.1 mol / 4-fluoroaniline in 200 ml dichloromethane at -60-65 ° C with stirring, dropwise 10.8 g / 0.1 mol tert-butyl hypochlorite in 25 ml dichloromethane stirring was continued at -60-65 ° C for 10 minutes and then added dropwise to the mixture.

A solution of 13.4 g (0.1 mol) of ethyl 2-methylthioacetate in 25 ml of dichloromethane is added at -60 ° C, stirring is continued for another hour, then at -60-65 ° C dropwise, A solution of 1 g (0.11 mol) of trimethylamine in 25 ml of dichloromethane is added. The cooling mixture is removed and 100 ml of water are added when the reaction mixture reaches room temperature. The phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in diethyl ether (350 mL) and treated with 2N hydrochloric acid (40 mL). The mixture was stirred overnight at room temperature. The phases were separated and the ether layer was washed with water and brine. The solid was recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, m.p.

ANALYSIS:

calculated. C, 54.80; H, 4.09; N, 7.10%; Found: C, 54.74; H, 4.11; N, 7.118 ° / o.

A sample of the above 5 fluoro-3-methylthio-2-oxindole (986 mg, 5.0 mmol / 50 mL alcohol) was added to two teaspoons of Raney Nickel and the reaction mixture was refluxed for 2 hours. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue dissolved in dichloromethane. The dichloromethane solvent was dried over sodium sulfate and concentrated in vacuo to give 475 mg of m.p.

5-Fluoro-2-oxindole is obtained.

In an analogous manner, 4-trifluoromethylaniline is terebutyl hypochlorite, ethyl 2 / methylthio /

-acetate and triethylamine and a

3-Thiomethyl-5-trifluoromethyl-2-oxindole Raney nickel reduction yields 189.5-190.5 ° C of 5-trifluoromethyl-2-oxindole.

example

Fluoro-5-methyl-2-oxindo!

11.62g / 57.6mmol · N- (2-chloro-acetyl / 3-fluoro-4-methylaniline and 30.6g / 229.5mmol / anhydrous aluminium chloride) mixed thoroughly 210-220 ° C After 4 hours, the reaction mixture was cooled and added to a mixture of 100 ml of 1N hydrochloric acid and 50 ml of ice. The resulting bronze-brown solid was collected by filtration and recrystallized from aqueous ethanol to give three crystalline generations of 4.49 g, 2.28 g oss 1.0. The first two generations were a mixture of isomers (4-fluoro-5-methyl and 6-fluoro-5-methyl-2-oxindoles). Recrystallized from 1.0 g of the third generation water gives the title compound 168.5 171 Con 280 mg

Example 36

Phenyl 2 oxindo!

Dimethyl sulfoxide (50 mL) was added to 3.46 g / 0.072 mol / L sodium hydride, and 8.2 mL / 0.072 mol · · dimethyl malonate dissolved in 10 mL of dimethyl sulfoxide was added dropwise with stirring. After the addition was complete, stirring was continued for 1 hour. A solution of g '0.036 mol / 4 bromo 3 nitrodiphenyl in 50 ml of dimethyl sulfoxide was added. The reaction mixture was heated to 100 ° C, maintained at this temperature for 1 hour, cooled and finally poured into ice water containing 5 g of ammonium chloride. The mixture is extracted with ethyl acetate, the extract is washed with sodium chloride solution, and the residue is taken up in magnesium sulfate. Concentration in vacuo gave an oil which was chromatographed on silica gel and recrystallized from methanol to give 6 g of dimethyl 2- (3-nitro-4-diphenyl) malonate, m.p.

Part of the above nitro compound / 5 g / platinum catalyst in 50 ml tetrahydrofuran and

-9194825 ml of methanol with hydrogen at about 5 kg / cm ² is reduced to the corresponding amine. The latter compound is refluxed in ethanol for 16 hours and the product is recrystallized from methanol to give 1.1 g of ethyl 6 phenyl 2 oxindole 1 carboxylate, m.p. 115-117 ° C.

1.0 g of the above ethyl ester is refluxed with 100 ml of 6N hydrochloric acid for 3 hours and then allowed to stand at room temperature for 3 days. The precipitated solid is filtered off to give 6-phenyl-2-oxindole (700 mg, 175-176 ° C).

Example 37

Acetyl 2 oxindole ml of carbon disulphide was treated with 27 g / 0.202 mol / l of aluminum chloride and a solution of 3 ml / 0.042 mol / acetyl chloride in 5 ml of carbon disulphide was added dropwise with stirring for a further 5 min and then 4.4 g / ml. Oxindole (0.033 mol / 2) was added. The resulting mixture was refluxed for 4 hours and then cooled. The carbon disulphide was removed by decantation and the residue was triturated with water and filtered. After drying, 3.2 g of the title compound was obtained, m.p. 225-227 ° C.

The oxindole 2 is reacted with bezoyl chloride and 2 tenoyl chloride in the presence of aluminum chloride essentially as described above to give the following two compounds:

benzoyl -2-oxindole, m.p. 203 205 C (from methanol) and

5/2 tenoyl / 2 oxindole. m.p. 211 213 C / acetonitrile /

Example 38 Bromo oxindole 2 can be prepared by bromination of oxindole 2; see further Beckett et al., Tetrahedron, 24, 6093, (1968) and Sumpter et al., J of the Am. Chem. Soc., 67, 1656 (1945), η-butyl 2-oxindole 5 n-butylisaline hydrazine hydrate followed by reaction with sodium methoxide in ethanol according to the procedure described in Preparation 1. 5 n Butyl isatin can be prepared from 4-n-butylaniline by treatment with chlorohydrate and hydroxyl amino, followed by sulfuric acid ring closure. The process is described in Preparation 3, Chapters A and B.

ethoxy-2-oxindole by standard methods of 3 hydroxy-6-nitrotoluene / conversion of potassium carbonate and ethyl iodide in acetone / 3 ethoxy-6 to nitrotoluene, followed by Beckett et al. al., Tetrahedron, 24, 6093 (1968), prepared using the method described for the conversion of 3-methoxy nitro toluene to 5-methoxy-oxindole.

5.6 Dimethoxy-2-oxindole is prepared as described in Walker, J. Am. Chem. Soc., 77, 3844 (1955), chloro-2-oxindole. It may be prepared according to the procedure described in United States Patent 5,268,684.

The 4-thiomethyl-2-oxindole and the 6-thiomethyl-2-oxine italic may be prepared according to the procedure described in U.S. Patent No. 4,006,161. 5-n-Butylthio-2-oxindole can be prepared in a similar fashion, but 3-methylthio-aniline must be equipped with 4-butylthio-aniline.

5,6-Methylenedioxy-2-oxindole may be prepared by the method described by McEvoy et al., J. Org Chem., 38, 3350 (1973). 5,6-ethylenedioxy-2-oxindole can be prepared analogously.

fluorine 2 oxindole Protiva et al. Collection of Czechoslovakian Chem. Communications, 44, 2108 (1979) and 4,160,032. It may be prepared according to the procedure described in U.S. Pat.

6-Trifluoromethyl-2-oxindole Schmid, J. Org. Chem., 28, 3580 (1963)

Methoxy-2-oxindole 6 is described in Wieland et al. Chem. Berichte, 96, 253/1963 //.

5-nitro-2-oxindole according to Sumpter et al., J. Am.ChemSoc, 67, 499/1945 //.

5-cyclopropyl 2-oxindole and 5-cycloheptyl 2-oxindole are prepared by reacting 5-cyclopropyl isatin and 5-cycloheptyl isatin with hydrazine hydrate followed by ethanolic sodium methoxide according to the procedure described in Preparation 1 for 5 cyclopropyl isatin and 5 cycloheptyl. isatin may be prepared from 4 cyclopropyl aniline and 4-cycloheptyl aniline by treatment with chloral hydrate and hydroxylamine followed by ring closure with sulfuric acid as described in Example 32 A and B

Example 39

5-Amino-2-oxindole-1-carboxamide

To a solution of 5.0 g of 5-nitro-2-oxindole 1 carboxamide in 110 ml of N, N dimethylformamide is added 0.5 g of 10% palladium on carbon and the resulting mixture is shaken under a hydrogen atmosphere of 5 kg / cm ² while hydrogen uptake stops. The catalyst was filtered off, the filtrate was diluted with brine and extracted with ethyl acetate. colored solid.

Example 2/2-Drilled / -2 Oxindole

To a solution of 5.5 g / 0.24 mol / sodium in 150 ml ethanol with stirring at room temperature

2-Oxindole (13.3 g, 0.10 mol) was added. The resulting slurry was cooled to ice water bath, and 15.7 g .0.12 mol / 2 drilled chloride was added dropwise over 10-15 minutes. The ice bath was removed, ethanol (100 mL) was added and the reaction mixture was refluxed for 7 hours. After standing overnight, the desired solid was filtered off. The filtered solid was added to 400 mL of water and the resulting mixture was washed with concentrated hydrochloric acid.

-10Ι9 to acidify. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid

8.3 g of melting yellow crystals at 209 ° C (dec) are obtained.

Analysis calculated for C13 H9 O3 N: C, 68.72; H, 3.99; N, 6.17%; Found: C, 68.25; H, 4.05; N, 6.20%.

The oxindole 2 is reacted with the appropriate acid chloride according to the above procedure to give the following products:

2-tenoyl / 2-oxindole, m.p. 189-190 'C, 17%;

/ 2 - [2-thienyl / acetyl / -2-oxindole, m.p.

192.5 ° C, yield 38 ° C, and 2 phenoxyacetyl / 2-oxindole, m.p. 135-136 ° C, 42% yield.

Example 41

3- / 3 Furoill 2 oxindole

To a solution of 2.8 g / 0.12 mol / sodium in 200 ml of ethanol was added 13.3 g / 0.10 mol / 2 of oxindole and 16.8 g of ethyl 3 furoate under stirring. The mixture was refluxed for 47 hours, and the solvent was evaporated in vacuo. The residue was triturated with ether (200 mL) and the solid was removed by filtration. The solid crude was slurried in 290 mL of water, acidified with concentrated hydrochloric acid and stirred to give a solid which was filtered. The solid was recrystallized from acetic acid followed by acetonitrile to give 705 mg of the title compound, m.p. 185-186 ° C.

Analysis calculated for C13 H9 O3 N: C, 68.72; H, 3.99; N, 6.17%;

Found: C, 68.72; H, 4.14; N, 6.14%.

Example 42

5-Chloro -3- (2-tenoyl / -2-oxindole) 1-carboxamide

21.1 g / 0.1 mol / 5 chlorine 2 oxindole from 1 arm boxanide and 26.9 g / 0.22 mol / 4 / N, N dimethylamino / pyrindine in 200 ml N, N dimethyl boron amide slurry under stirring After cooling to an ice water bath, 16.1 g (0.11 mol) of N, N dimethylformamide in 50 ml

2-Tenoyl chloride is added dropwise. Stirring is continued for about 30 minutes, then the reaction mixture is poured into a mixture of 1 liter of water and 75 ml of 3N hydrochloric acid solution. 230 C (dec.).

A sample of the title compound from a similar lesion gave two results:

Elemental analysis based on the formula C14H9CIN2O3S:

Calc'd: C, 52.42; H, 2.83; N, 8.74%; Found: C, 52.22; H, 2.81; N, 8.53%.

Example 43

The corresponding oxindole carboxamide 2 is reacted with the requisite acid chloride RCO Cl in essentially the same manner as in Example 42 to give the compounds of the general formula (VIII):

XR 'Op / C / ¹² Elemental analysis calculated ° / c% found

C H N C H N 5 Cl 2-furyl 234d 55.18 2.98 9:20 5506 3:09 9:32 5-Cl 2-'2-thienyl. -methyl 240C 53.81 3:31 8:37 53.40 3:31 8:37 6-Cl 2-furyl 218-219 55.19 2.98 9:19 54.89 2.90 9:23 6-Cl 2-thienyl 201-202 52.44 2.83 8.74 61.86 3.03 8.61 6-Cl 2- / 2-methyl-tienil. 219-220 5383 3:31 8.37 53.70 3:45 8:38 5-F 2-furyl 232D 58.34 3:15 9.72 57.99 3:13 9.70 5-F 2 way 231D 55.25 2.98 9:21 55.49 3.00 9:28 5-F 2-'2-thienylmethyl 243D 56.59 3.48 880 56.76 3:48 8.81 6-F 2-furyl 230.5-233.5 58.33 3:13 9.75 57.73 3:04 9.72 6 F 2 way 117,5-120.5 55.26 2.96 9.21 55.14 2.91 9.15 6-F 2- / 2-thienyl methyl .'- 214.5-217 56.61 3.48 8.80 55.97 3.52 8.65 5-CF3 2-furyl 235.5d 53.26 2.68 8:28 52.84 2.96 8:17 5-CF3 2-thienyl 212.5d 50.85 2.56 7.91 50.43 2.72 7.90 5-CFj 2- / 2-thienyl, '- methyl 223.5 52 17 3:01 7.61 51.72 3:37 7.45 6-CF3 2-furyl 206-208 53.26 2.68 8:28 52.87 3:03 8:27 6-CF3 2-thienyl 177-180 50.86 2.56 7.91 50.69 2.75 7.96

Explanation:

₂ all compounds were recrystallized from acetic acid unless otherwise indicated: in this case and in the column, "d" indicates that the compound melts during decomposition; Recrystallized from NN-dimethylformamide.

Example 44

Chlorine 3-acetyl 2 oxindole 1 carboxamide

A slurry of 842 mg / 4.0 mmol / 5 chloro-2-oxindole arm boxamide and 1.08 g / 8.8 mmol / 4 / N, N-dimethylamino / pyridine in 15 ml NN dimethylformamide was cooled to ice bath temperature with stirring. . A mixture of 449 mg / 4.4 mmol acetic anhydride in 5 ml of Ν, Ν-dimethylformamide was added dropwise. The stirring was continued for a further 30 minutes and the reaction mixture was treated with 75 ml

Pour into a mixture of 3N hydrochloric acid. The resulting mixture was cooled in an ice-water bath and the precipitated solid was filtered off.

-11194825

Elemental analysis for C11H9CIN2O3: Calcd. C, 52.29; H, 3.59; N, 11.09%; Found: C, 52.08; H, 3.63; N, 11.04%

Claims (15)

PATENT CLAIMS A process for the preparation of compounds of formula (111) in which X is hydrogen, fluoro, chloro, bromo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, nitro, phenyl, C 2-4 alkanoyl, benzoyl or tenoyl, Y is hydrogen, fluoro, chloro, C14 alkyl, C14 alkoxy, or X and Y together are the methylene dioxy group attached to the adjacent carbon atoms, R is a hydrogen atom or a CO R group in which R 4 is furyl, lienyl or thienyl (C 1 -C 3) alkyl, characterized in that a compound of formula (II) wherein X, Y and R are as above is hydrolyzed (Preferred: 12.12.1984). A process according to claim 1 for the preparation of compounds of the general formula III in which X is hydrogen, fluoro, chloro, bromo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoromethyl, nitro, Y is hydrogen, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or X and Y together are the methylene dioxy group attached to the adjacent carbon atoms, R is hydrogen or - CO R group in which R 'is furyl. may be thienyl or thienyl / C 1 -C 3 / alkyl, characterized in that it is based on appropriately substituted materials / Process according to claim 1, characterized in that the hydrolysis is carried out essentially only with water. December 21, 1984 / The process according to claim 2, wherein the hydrolysis is substantially water-only. / Priority: March 19, 1984/ Process according to claim 1, characterized in that the hydrolysis is carried out with an aqueous solution of an inorganic or organic acid. Priority 21.12.1984 / The process according to claim 2, wherein the hydrolysis is carried out with an aqueous solution of an inorganic or organic acid Priority 19.03.1984 / The process of claim 5 wherein the inorganic or organic acid is hydrochloric acid, sulfuric acid, phosphoric acid, vinegar 12 watts. formic acid is used with citric acid or benzoic acid / Priority: I984 12 21 / A process according to claim 6 wherein the inorganic or organic acid is sulfuric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, citric acid or benzoic acid. Process according to any one of claims 5 and 7, characterized in that the organic or organic acid is used in a concentration range of 1 mol to 6 mol / Priority: 21.12.1984 / Process according to any one of claims 6 and 8, characterized in that the organic or organic acid is used in a concentration range of from 1 mol to 6 mol. / Priority. 19.03.1984 / 11. A process according to any one of claims 1 to 6 for the preparation of compounds of formula III wherein: X is hydrogen, 5-chloro, 5-fluoro or 5 trifluoromethyl groups, Y is hydrogen, 6 chlorine, 6-fluorine 6 trifluoromethyl groups: and R is hydrogen, characterized in that it is derived from appropriately substituted materials. A process according to claim 11 for the preparation of compounds of formula III wherein: X 5 chlorine and R and Y are hydrogen, characterized in that they are derived from appropriately substituted materials. / Priority: 19.03.1984 / A process according to any one of claims 1 to 10 for the preparation of compounds of formula III wherein X is hydrogen, 5 is chlorine, 5 is fluorine or trifluoromethyl, Y is hydrogen, 6 chloro, 6 fluoro or 6 trifluoro methyl: and RCO is a group of the formula R ¹ wherein R ¹ is 2-furyl, 2-thienyl group or / 2 thienyl / methyl, characterized in that the starting material according to is substituted at / Priority 03 19 1984 / A process according to claim 13 for the preparation of compounds of formula III wherein X 5 chlorine, Y is hydrogen RR CO is and R 2 is thienyl, characterized in that it is derived from appropriately substituted materials. / Priority March 19, 1984 / A process according to any one of claims 1 to 10 for the preparation of compounds of formula III wherein: -12194825 X is fluorine, Y 6 is chlorine and R is hydrogen, characterized in that it is based on appropriately substituted materials Priority. 03 Mar 1984. 197 2 sheets of drawing with pictures